EP0846117B1 - Procede de preparation de derives de biphenyle - Google Patents
Procede de preparation de derives de biphenyle Download PDFInfo
- Publication number
- EP0846117B1 EP0846117B1 EP96918189A EP96918189A EP0846117B1 EP 0846117 B1 EP0846117 B1 EP 0846117B1 EP 96918189 A EP96918189 A EP 96918189A EP 96918189 A EP96918189 A EP 96918189A EP 0846117 B1 EP0846117 B1 EP 0846117B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- tert
- butyl
- formula
- palladium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title description 22
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 73
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- -1 p-methoxybenzyl group Chemical group 0.000 claims abstract description 55
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims abstract description 47
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 36
- 239000003054 catalyst Substances 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 239000011592 zinc chloride Substances 0.000 claims abstract description 23
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 21
- 235000005074 zinc chloride Nutrition 0.000 claims abstract description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 13
- VNDYJBBGRKZCSX-UHFFFAOYSA-L Zinc bromide Inorganic materials Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims abstract description 9
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims abstract description 7
- 229940102001 zinc bromide Drugs 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 41
- 239000002904 solvent Substances 0.000 claims description 33
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 229910052749 magnesium Inorganic materials 0.000 claims description 24
- 239000011777 magnesium Substances 0.000 claims description 24
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 21
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- 150000004795 grignard reagents Chemical class 0.000 claims description 15
- 238000011065 in-situ storage Methods 0.000 claims description 14
- 125000006239 protecting group Chemical group 0.000 claims description 12
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 10
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 10
- 125000001246 bromo group Chemical group Br* 0.000 claims description 9
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 150000002170 ethers Chemical class 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
- NIYHSSNWRHDRPB-UHFFFAOYSA-M CC(C)(C)N1N=NC(C=2C(=CC=CC=2)[Zn]Br)=N1 Chemical compound CC(C)(C)N1N=NC(C=2C(=CC=CC=2)[Zn]Br)=N1 NIYHSSNWRHDRPB-UHFFFAOYSA-M 0.000 claims description 5
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 claims description 5
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims description 5
- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 claims description 5
- WGJUUNXZYPXXCS-UHFFFAOYSA-N 5-(2-bromophenyl)-2-tert-butyltetrazole Chemical compound CC(C)(C)N1N=NC(C=2C(=CC=CC=2)Br)=N1 WGJUUNXZYPXXCS-UHFFFAOYSA-N 0.000 claims description 4
- 238000002955 isolation Methods 0.000 claims description 4
- 150000002815 nickel Chemical class 0.000 claims description 4
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 4
- 239000001294 propane Substances 0.000 claims description 4
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 3
- XXECWTBMGGXMKP-UHFFFAOYSA-L dichloronickel;2-diphenylphosphanylethyl(diphenyl)phosphane Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 XXECWTBMGGXMKP-UHFFFAOYSA-L 0.000 claims description 3
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical compound [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 claims description 3
- ZBRJXVVKPBZPAN-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dichloride Chemical compound [Cl-].[Cl-].[Ni+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 ZBRJXVVKPBZPAN-UHFFFAOYSA-L 0.000 claims description 3
- 230000000717 retained effect Effects 0.000 claims description 3
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000009977 dual effect Effects 0.000 claims description 2
- 125000002346 iodo group Chemical group I* 0.000 claims description 2
- 125000006303 iodophenyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- DGLXYWWKKFMOIK-UHFFFAOYSA-N 5-bromo-1-tert-butyltetrazole Chemical compound CC(C)(C)N1N=NN=C1Br DGLXYWWKKFMOIK-UHFFFAOYSA-N 0.000 description 27
- 239000010410 layer Substances 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 19
- 239000000725 suspension Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 238000006880 cross-coupling reaction Methods 0.000 description 11
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000000908 ammonium hydroxide Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 6
- 229910052759 nickel Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- OJVAMHKKJGICOG-UHFFFAOYSA-N 2,5-hexanedione Chemical compound CC(=O)CCC(C)=O OJVAMHKKJGICOG-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 150000001499 aryl bromides Chemical class 0.000 description 4
- 239000012258 stirred mixture Substances 0.000 description 4
- 0 *c(cc1)ccc1-c1n[n](*)nn1 Chemical compound *c(cc1)ccc1-c1n[n](*)nn1 0.000 description 3
- RIGIQZIXVFCURM-UHFFFAOYSA-N 8-[(4-bromophenyl)methyl]-2,4-dimethyl-5,6-dihydropyrido[2,3-d]pyrimidin-7-one Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC1=CC=C(Br)C=C1 RIGIQZIXVFCURM-UHFFFAOYSA-N 0.000 description 3
- NTNODCYFAGKBNL-UHFFFAOYSA-M CC(C)(C)N1N=NC(C=2C(=CC=CC=2)[Zn]Cl)=N1 Chemical compound CC(C)(C)N1N=NC(C=2C(=CC=CC=2)[Zn]Cl)=N1 NTNODCYFAGKBNL-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 150000001502 aryl halides Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- 238000010651 palladium-catalyzed cross coupling reaction Methods 0.000 description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 150000003536 tetrazoles Chemical class 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 229910002666 PdCl2 Inorganic materials 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- VNMANZNPIXMPRL-UHFFFAOYSA-M [Cl-].[Zn+]C1=CC=CC=N1 Chemical class [Cl-].[Zn+]C1=CC=CC=N1 VNMANZNPIXMPRL-UHFFFAOYSA-M 0.000 description 2
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 2
- 125000004849 alkoxymethyl group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 150000005347 biaryls Chemical class 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- KZIBQYUFIVUOHY-UHFFFAOYSA-N bis(2-methylpropyl)alumane toluene Chemical compound Cc1ccccc1.[H][Al](CC(C)C)CC(C)C KZIBQYUFIVUOHY-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- 238000006478 transmetalation reaction Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- NWAUPHAHIDQCHS-UHFFFAOYSA-N 1,1'-biphenyl;2h-tetrazole Chemical class C1=NN=NN1.C1=CC=CC=C1C1=CC=CC=C1 NWAUPHAHIDQCHS-UHFFFAOYSA-N 0.000 description 1
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 1
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 1
- UMHICUBOARRMLV-UHFFFAOYSA-N 2-(5-bromo-2-tert-butylphenyl)tetrazole Chemical compound CC(C)(C)C1=CC=C(Br)C=C1N1N=NC=N1 UMHICUBOARRMLV-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- RTHLAOFSIJMOCU-UHFFFAOYSA-N 3-(2-bromophenyl)-1-tert-butyl-2h-tetrazole Chemical compound N1=CN(C(C)(C)C)NN1C1=CC=CC=C1Br RTHLAOFSIJMOCU-UHFFFAOYSA-N 0.000 description 1
- KBTMGSMZIKLAHN-UHFFFAOYSA-N 4-bromo-1,2-dimethoxybenzene Chemical compound COC1=CC=C(Br)C=C1OC KBTMGSMZIKLAHN-UHFFFAOYSA-N 0.000 description 1
- KHMJZQFKDOBODS-UHFFFAOYSA-N 5-(2-bromophenyl)-1-trityltetrazole Chemical group BrC1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KHMJZQFKDOBODS-UHFFFAOYSA-N 0.000 description 1
- KUGPFSZEGMEJKL-UHFFFAOYSA-N 5-bromo-1-butyltetrazole Chemical compound CCCCN1N=NN=C1Br KUGPFSZEGMEJKL-UHFFFAOYSA-N 0.000 description 1
- WGNYOCAOLVBRDL-UHFFFAOYSA-N 6-pyridin-2-yl-1h-quinolin-2-one Chemical class C=1C=C2NC(=O)C=CC2=CC=1C1=CC=CC=N1 WGNYOCAOLVBRDL-UHFFFAOYSA-N 0.000 description 1
- PKXFTEXAADGGLM-UHFFFAOYSA-N 8-[[4-[2-(1-tert-butyltetrazol-5-yl)phenyl]phenyl]methyl]-2,4-dimethyl-5,6-dihydropyrido[2,3-d]pyrimidin-7-one Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C)(C)C PKXFTEXAADGGLM-UHFFFAOYSA-N 0.000 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- CBEKIHJTHNURLG-UHFFFAOYSA-M CC(C)(C)N1N=NC(C=2C(=CC=CC=2)[Mg]Br)=N1 Chemical compound CC(C)(C)N1N=NC(C=2C(=CC=CC=2)[Mg]Br)=N1 CBEKIHJTHNURLG-UHFFFAOYSA-M 0.000 description 1
- SLZKQTBUTFMIQN-UHFFFAOYSA-N COC1=CC=C([Zn])C=C1OC Chemical compound COC1=CC=C([Zn])C=C1OC SLZKQTBUTFMIQN-UHFFFAOYSA-N 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- UNKQVRFPUYCEJA-UHFFFAOYSA-N [Zn]CC1=CC=CC=C1 Chemical class [Zn]CC1=CC=CC=C1 UNKQVRFPUYCEJA-UHFFFAOYSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000091 aluminium hydride Inorganic materials 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- UZZWBUYVTBPQIV-UHFFFAOYSA-N dme dimethoxyethane Chemical compound COCCOC.COCCOC UZZWBUYVTBPQIV-UHFFFAOYSA-N 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- WUOIAOOSKMHJOV-UHFFFAOYSA-N ethyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(CC)C1=CC=CC=C1 WUOIAOOSKMHJOV-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- JDOZOOBCADNBIJ-UHFFFAOYSA-N lithium;2h-pyridin-2-ide Chemical compound [Li+].C1=CC=N[C-]=C1 JDOZOOBCADNBIJ-UHFFFAOYSA-N 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- AAOYMMGISWFRLA-UHFFFAOYSA-N methyl 3-bromo-4-(3,4-dimethoxyphenyl)benzoate Chemical compound BrC1=CC(C(=O)OC)=CC=C1C1=CC=C(OC)C(OC)=C1 AAOYMMGISWFRLA-UHFFFAOYSA-N 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- KFBKRCXOTTUAFS-UHFFFAOYSA-N nickel;triphenylphosphane Chemical compound [Ni].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 KFBKRCXOTTUAFS-UHFFFAOYSA-N 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This invention concerns an improved process for production of inter alia the intermediate 8-[2'-(2(1)-tert-butyl-2H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-2,4-dimethyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one, which is the precursor to the product drug substance 5,8-dihydro-2,4-dimethyl-8-[(2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]pyrido[2,3-d]pyrimidin-7(6H)-one.
- Said product drug substance is an angiotensin II antagonist, particularly useful as an antihypertensive agent, which is disclosed in U.S. Patent No. 5,149,699 (American Home Products Corporation).
- the process disclosed herein utilizes a Grignard reaction with, for example, a 1-(t-butyl)-3-(2-bromophenyl)tetrazole to produce the t-butylphenyltetrazole-2-magnesium bromide Grignard reagent rather than such ortho-lithiated reactant A which is then transmetallized with zinc chloride.
- the process disclosed herein therefore avoids the use of pyrophoric butyllithium.
- Steps 3, 4 and 5 -of Example 3 of the said U.S. patent 5,149,699 discloses the preparation of the subject intermediate, ⁇ also known as 2,4-Dimethyl-5,6,8-trihydro-8-[[2'-(1-tert-butyl-1 H -tetrazol-5-yl)[1,1-biphenyl]-4-yl]methyl]-7 H -pyrido[2,3-d]pyrimidin-7-one, ⁇ by the following reaction sequence: As seen from the above schematic, the 2-t-butyl-5-bromophenyl-2H-tetrazole, referred to hereinafter as "t-butylbromotetrazole", (1) is reacted with magnesium to produce the corresponding Grignard reagent which is then further reacted to produce the boronic acid (2).
- t-butylbromotetrazole 2-t-butyl-5-bromophenyl-2H-tetrazole
- the overall yield for these step is 48%.
- the palladium catalyzed cross-coupling of the boronic acid (2) and the 8-[(4-bromophenyl)-methyl]5,8-dihydro-2,4-dimethyl-pyrido[2,3-d]pyrimidin-7(6H)-one, referred to hereinafter as "bromobenzyl lactam", (3) afford the subject intermediate in 66% yield.
- the process disclosed herein surprisingly provides better yields and avoids the isolation of the boronic acid (2).
- Example 5 of the European patent EP 0550313A1 (Synthelabo) describes the preparation of the biphenyl product (5) by the following sequence.
- the aryl bromide (4) is converted to an organozinc which is used in the cross-coupling reaction to afford the biphenyl product (5) in yield ranging from 60 to 80%.
- the Gagnard reagent is prepared from the aryltetmzole. This is an advantage since the arylhalide which does not contain the tetrazole ring can be fully functionalized.
- Example 90 The only specific illustration of this reaction is in Example 90 where M is -MgBr and R 40 is bromo, that is, the tetrazole reactant is 5-(2-bromophenyl)-1-(triphenylmethyl)-1H-tetrazole, and the quinazolinone mactant is 3-[4-bromophenyl)methyl]-2-butyl-6-(1-methoxy-1-methylethyl)-4(3H)-quinazolinone].
- a process for preparing a compound of the formula I: or a salt thereof wherein X is a protecting group and R 1 , R 2 , R 3 and R 4 are each independently hydrogen, C 1-6 alkyl or C 1-6 perfluoroalkyl, R 5 is hydrogen or R 5 taken together with R 3 forms a double bond; m is 1, 2 or 3; n is 0 or 1, and p is 0, 1 or 2; by
- protecting group' denotes a group which remains in position whilst a reaction (such as Grignard formation, transmetallization and/or coupling) is carried out, but can be readily removed thereafter, for example by acid or base hydrolysis.
- protecting groups include tert-butyl, C 1-4 alkoxymethyl, methylthiomethyl, phenyl C 1-4 alkoxymethyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl, 2-(trimethylsilyl)ethyl, tetrahydropyranyl and piperanyl.
- X is a C 1-6 alkyl group or a phenyl or benzyl group, in each case optionally substituted by one or more substituents selected from C 1-6 alkyl (eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl), C 1-6 alkoxy (eg methoxy, ethoxy, propoxy, butoxy), nitro, amino, (C 1-6 )alkylamino, di(C 1-6 )alkylamino, thio(C 1-6 )alkyl or phenyl substituents; or a benzyloxymethyl group optionally substituted on the phenyl ring by one or more substituents selected from C 1-6 alkyl (eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl), or C 1-6 alk
- X is a C 1-6 alkyl group optionally substituted by by one or more substituents selected from C 1-6 alkoxy (eg methoxy, ethoxy, propoxy, butoxy), nitro, amino, (C 1-6 )alkylamino, di(C 1-6 )alkylamino or thio(C 1-6 )alkyl.
- C 1-6 alkoxy eg methoxy, ethoxy, propoxy, butoxy
- nitro amino
- (C 1-6 )alkylamino di(C 1-6 )alkylamino or thio(C 1-6 )alkyl.
- X is a branched chain alkyl group such as tert-butyl.
- n is 1
- p is 1
- R 1 and R 2 are each methyl and R 3 and R 4 are each hydrogen.
- R 6 is bromo
- R 8 is MgBr.
- R 9 is bromo
- the palladium or nickel catalyst is generated from a palladium or nickel salt, a reducing agent and a ligand or from a palladium or nickel salt and a species having dual reducing agent/ligand functions or from a palladium or nickel complex and a ligand.
- the catalyst is generated from Pd(OAc) 2 or PdCl 2 (PPh 3 ) 2 NiCl 2 (dppe), NiCl 2 (PPh 3 ) 2 , Ni(acac) 2 or Pd 2 (dba) 3 and one or more reducing agents/ligands selected from the group consisting of PPh 3 , P(o-tolyl) 3 , P(t-butyl) 3 , P(2-furyl) 3 , P(OiPr)3, CuI, CuBr, AsPh 3, N 2 H 4 and diisobutylaluminum hydride (DIBAL), 1,3-(diphenylphosphino)propane (DPPP) or bis (1,4-diphenylphosphino)butane (DPPB).
- DIBAL diisobutylaluminum hydride
- DPPP 1,3-(diphenylphosphino)propane
- DPPB 1,4-diphenylpho
- the catalyst is generated in situ in the reaction vessel in which the reaction of the compounds of formulae II and III is carried out.
- reaction of the compounds of formulae II and III and the transmetallization of the compound of formula IV is carried out in the presence of a solvent species which is substantially immiscible with water, suitably a hydrocarbon solvent, and preferably an aromatic hydrocarbon solvent such as toluene or xylene.
- a solvent species which is substantially immiscible with water suitably a hydrocarbon solvent, and preferably an aromatic hydrocarbon solvent such as toluene or xylene.
- the reaction of the compounds of formulae II and III and the transmetallization of the compound of formula IV is carried out in the presence of a mixture of solvent species which includes a solvent species which is substantially immiscible with water and a solvent species in the form of an ether.
- a mixture of solvent species which includes a solvent species which is substantially immiscible with water and a solvent species in the form of an ether is from 5:1 to 1:5.
- the solvent species in the form of an ether is tetrahydrofuran (THF).
- zinc chloride is used as the transmetallizing agent.
- the solvent which is substantially immiscible with water will have a low polarity, and may be substantially non-polar.
- reaction of the compound of formulae IV and in situ generation of the palladium or nickel catalyst are carried out substantially in the same reaction vessel.
- reactions of the compounds of formulae II, III and IV and in situ generation of the palladium or nickel catalyst are carried out substantially in the same reaction vessel.
- the compound of formula IV is prepared by reacting a compound of formula V: or a salt thereof; wherein X is a protecting group and R 9 is Br or I; with magnesium.
- reaction of the compound of formula V with magnesium is carried out in the presence of a solvent in the form of an ether such as THF, dimethoxyethane (DME), diethylether or 1,4-dioxan, of which THF is preferred.
- a solvent in the form of an ether such as THF, dimethoxyethane (DME), diethylether or 1,4-dioxan, of which THF is preferred.
- At least a portion of the ether solvent present during the reaction of the compound of formula V with magnesium is retained during the reaction of the compound of formula IV with the transmetallizing agent and suitably at least a portion of the ether solvent present during the reaction of the compound of formula V with magnesium is retained during the reaction of the compounds of formula II and III.
- the process comprises the further step of deprotecting the compound of formula I to provide a compound of formula VI: or a salt thereof; wherein R 1 , R 2 , R 3 and R 4 are each independently hydrogen, C 1-6 alkyl or C 1-6 perfluoroalkyl, R 5 is hydrogen or R 5 taken together with R 3 forms a double bond; m is 1, 2 or 3; n is 0 or 1, and p is 0, 1 or 2.
- the invention provides a process for producing 8-[2'-(2(1)-tert-butyl-2H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-2,4-dimethyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (or such a compound wherein a benzyl or p-methoxybenzyl group is present in place of the tert-butyl group) or a salt thereof, said process characterized in
- step A Preferably 2-tert-butyl-5-(2-bromophenyl)-2H-tetrazole is used in step A.
- zinc chloride is the transmetallizing agent in step B.
- the Grignard reagent is prepared by reacting 2-tert-butyl-5-(2-bromophenyl)-2H-tetrazole with magnesium.
- a palladium catalyst is used in step C.
- the palladium catalyst is generated from PdCl 2 , Pd(OAc) 2 , Pd 2 (dba) 3 , or PdCl 2 (PPh 3 ) 2 and an additive selected from the group consisting of PPh 3 , P(o-tolyl) 3 , P(2-furyl) 3 , P(t-butyl) 3 , P(OiPr) 3 , CuI, CuBr, AsPh 3 , DPPP, DPPB and DIBAL.
- a palladium catalyst is generated in the reaction vessel containing the chloro or bromo[2-[2-(tert-butyl)-2H-tetrazol-5-yl]phenyl]zinc.
- steps B and C and the generation of the palladium or nickel catalyst are carried out in the same reaction vessel.
- the invention provides a method for producing 8-[2'-(2(1)-tert-butyl-2H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-2,4-dimethyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (or such a compound wherein a benzyl or p-methoxybenzyl group is present in place of the tert-butyl group) or a salt thereof, said process characterized in:
- the process comprises the further step of deprotecting the product to provide 8-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-2,4-dimethyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one or a salt thereof.
- the invention provides compound of the formula VII: or a salt thereof wherein R 10 is a C 1-6 alkyl group and R 11 is ZnCl or ZnBr.
- R 10 is a branched chain alkyl group such as tert-butyl.
- a preferred process of the invention for production of the intermediate 8-[2'(2(1)-tert-butyl-2H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-2,4-dimethyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one is shown in the following schematic diagram.
- the t-butylbromotetrazole (1) reacts with magnesium to produce the corresponding Grignardreagent (1a) which is treated with zinc chloride to afford the organozinc (2).
- the latter is not isolated and is treated with the bromobenzyl lactam (3) in presence of catalytic amount of palladium or nickel catalyst to produce the desired intermediate (4).
- Deprotection by known means for example by acid catalysed hydrolysis, eg using 2N HCl
- further crystallization as necessary, yields the desired drug substance product (5).
- suitable means of deprotection are described in U.S. Patent No. 5.149,699 to Ellingboe et al. (see eg Example 3, step 6; which is herein incorporated by reference) and in J.W. Ellingboe et al., J. Med. Chem. 1994, 37, 542-550.
- the protected compound may be mixed with an approximately ten molar excess of methanesulphonic acid in toluene and heated under reflux for about 18 hours.
- the mixture may then be concentrated and water and 1N KOH may be added to give a solution of pH 8.
- the resulting mixture may be extracted with ethyl acetate to remove unreacted starting material, and the aqueous phase may be acidified with 1N HCl to pH 5.
- the product may then be extracted into ethyl acetate and dried over MgSO 4 and concentrated and, if necessary triturated (eg with acetone/ether) to give the deprotected product as a solid.
- Particularly preferred is a process for producing 8-[2'-(2(1)-tert-butyl-2H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-2,4-dimethyl-5,8-dihydro-6H-pyrido[2,3-d]-pyrimidin-7-one or a salt thereof, said process characterized in
- the t-butylbromotetrazole (1) [or other compound of formula III] is preferably prepared and used in a molar excess of the bromobenzyl lactam (3) [or other compound of formula II] of 1- 2 to 1, preferably 1.1-1.4 to 1, and most preferably 1.2-1.3 to 1.
- the transmetallization agent is preferably used in a 1-3 to 1 molar ratio, preferably in a 1.5-3 to 1 molar ratio, most preferably in a 2-2.5 to 1 molar ratio to the amount of t-butylbromotetrazole (1) [or other compound of formula III].
- the palladium or nickel catalyst is preferably used in a 0.005-0.05 to 1 molar ratio, preferably in a 0.01-0.03 to 1 molar ratio, and most preferably in a 0.015-0.030 to 1 molar ratio to the bromobenzyl lactam (3) [or other compound of formula II].
- the solvent used in Step A is an ether, such as tetrahydrofuran (THF), dimethoxyethane (DME), diethyl ether, or dioxane, which may be used in Steps B and C (or more generally in reaction of compounds of formula II, III and IV).
- the preferred solvent in Step A is THF.
- an additional solvent in addition to a main solvent is added in step B (or more generally in reaction of compounds of formula IV), which additional solvent is preferably a a water immiscible solvent.
- the additional solvent is preferably present in a volume ratio of 0.1-5 to 1, preferably 0.3-4 to 1, most preferably 1-2 to 1, relative to the main solvent.
- the additional solvent is miscible with the main solvent but immiscible with water.
- the additional solvent is preferably hydrocarbon and more preferably an aromatic hydrocarbon solvent is preferred.
- the temperature is kept low in order to prevent reaction between the solvent and the transmetallizing agent, but sufficiently high to ensure that the reagents remain in solution.
- a suitable temperature range is 30 to 50°C, preferably 30 to 40°C
- the preferred temperatures for the cross-coupling step C are 50-70°C, and more preferably about 60-65°C.
- Steps B and C are preferably run in one reaction vessel without isolation of the transmetallization product of Step B (or more generally the compound of formula III).
- the generation of the catalyst is also carried out in the same rection vessel used for steps B and C (or more generally in reaction of compounds of formula II, III and IV).
- the palladium or nickel catalyst is in the zero oxidation state.
- the palladium or nickel catalyst may either be added pre-formed or may be generated in situ.
- Suitable pre-formed palladium and nickel catalysts for step C include Pd 2 dba 3 Ni(PPh 3 ) 4 , and Pd(PPh 3 ) 4 .
- the catalyst can be generated in situ by mixing Pd(OAc) 2 , PdCl 2 , PdCl 2 (PPh 3 ) 2 , NiCl 2 (dppe), NiCl 2 (PPh 3 ) 2 , Ni(acac) 2 or Pd 2 dba 3 with one or more ligand/reducing agents as additives, such as, PPh 3 , P(o-tolyl) 3 , P(t-butyl) 3 , P(2-furyl) 3 , P(OiPr) 3 , CuI, CuBr, AsPh 3 , DIBAL, dppp or dppb.
- Pd(OAc) 2 PdCl 2 , PdCl 2 (PPh 3 ) 2 , NiCl 2 (dppe), NiCl 2 (PPh 3 ) 2 , Ni(acac) 2 or Pd 2 dba 3
- one or more ligand/reducing agents as additives, such as,
- a particularly preferred in situ catalyst is generated by adding Pd(OAc) 2 and PPh 3 .
- acac acetonylacetone
- dba dibenzylidene acetone
- DIBAL diisobutylaluminum hydride
- dppp 1,3-(diphenylphosphino)propane
- dppb bis(1,4-diphenylphosphino)butane.
- the resulting layers layers were and 1821 g toluene was added to the organic layer and then 2.1 l 2N HCl. The resulting mixture was stirred for 30 minutes at 5°C. The resulting layers were separated and the organic layer was washed with 3 x 0.7 L 2N HCl. All of the 2N HCl layers were combined and stirred with 303 g toluenc. The layers layers were separated and 2428 g toluene were added to the aqueous layer, followed by 2.8 l concentrated ammonium hydroxide to the organic phase while maintaining the temperature 0-10°C. The layers were separated and the aqueous layer washed with 607 g toluene. The two organic layers were combined and washed with 2 x 350 ml water. The organic layer was dried over sodium sulfate and concentrated to an oil. 637 g of product, yield - 78% of crude product.
- Organozinc preparation Chloro[2-[2-(tert-butyl)-2H-tetrazol-5-yl]phenyl]-zinc
- t-butylbromotetrazole (1) 600 g was dissolved in 640 g tetrahydrofuran. 10% of this t-butylbromotetrazole solution was added to a stirred suspension of 72.6 g magnesium in 320 g tetrahydrofuran at 50°C. 3.27 g of 1,2-dibromoethane was added to the resulting mixture and the mixture was stirred 30 minutes at 50°C. The remainder of the t-butylbromotetrazole solution was added to the magnesium suspension at a steady rate over 6 hours.
- the resulting mixture was stirred a further 2 hours at 50°C, 3.27 g of 1,2-dibromoethane was added and stirring was continued at 50°C for another 5 hours.
- the resulting Grignard reagent mixture was cooled to 25°C. 527.2 g of zinc chloride was then dissolved in a mixture of 844 g toluene and 844 g of tetrahydrofuran. The Grignard reagent was added to the zinc chloride solution and the resulting suspension stirred for 15 minutes at 25°C to provide an organozinc mixture.
- the mixture was cooled to 25-30°C and added with water (40 g) and acetic acid (4.1 g).
- the organic phase was separated and washed with water (40 g).
- the organic phase was added with water (10 g) and 30% ammonium hydroxide (9.3 g); after separation of the phases, the organic layer was added with water (30 g) and acetic acid (about 1.66 g) until pH 5.
- the organic phase was separated and analysed by HPLC against an external standard (see Table 1).
- the mixture was cooled to 25-30°C and added with water (40 g) and acetic acid (4.2 g).
- the organic phase was separated and washed with water (40 g).
- the organic phase was added with water (10 g) and 30% ammonium hydroxide (9.3 g), separated and added again with water (30 g) and acetic acid (1.7 g) until pH5.
- the organic phase was separated and evaporated at 60°C under vacuum to give a residue which was dissolved in isopropyl alcohol (85 g) at 50°C.
- the solution was allowed to crystallize by slow cooling to -10°C and kept at this temperature overnight.
- the product was collected by filtration, washed with isopropyl alcohol and dried at 60°C under vacuum to yield 30 g of pure product (74.6% yield based on compound 3).
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Claims (33)
- Procédé de préparation d'un composé de formule I : ou d'un sel de celui-ci;
dans laquelle X est un groupement protecteur et R1, R2, R3 et R4 sont chacun indépendamment un hydrogène, un alkyle en C1-C6, ou un perfluoroalkyle en C1-C6, R5 est un hydrogène ou R5 pris conjointement avec R3 forme une double liaison; m est 1, 2 ou 3; n est 0 ou 1, et p est 0, 1 ou 2;
para) la réaction d'un composé de formule IV ou d'un sel de celui-ci;
dans laquelle X est un groupement protecteur et R8 est
MgBr ou MgI;
avec un agent de transfert de métal sélectionné parmi du chlorure de zinc ou du bromure de zinc pour donner un composé de formule (III) : ou un sel de celui-ci;
dans laquelle X est un groupement protecteur et R7 est
ZnCl ou ZnBr;
et
dans laquelle R1 à R5, m, n et p sont chacun comme définis ci-dessus et R6 est un chloro, un bromo ou un iodo, en présence d'un catalyseur de palladium ou de nickel. - Procédé suivant la revendication 1, dans lequel le catalyseur de palladium ou de nickel est généré à partir d'un sel de palladium ou de nickel, un agent réducteur et un ligand ou à partir d'un sel de palladium ou de nickel et une espèce présentant des fonctions doubles d'agent réducteur/ligand.
- Procédé suivant la revendication 2, dans lequel le catalyseur est généré à partir de Pd(OAc)2 ou de PdCl2(PPh3)2, de NiCl2(dppe), de NiCl2(PPh3)2, de Ni(acac)2 ou de Pd2dba3 et d'un ou plusieurs agents réducteurs/ligands sélectionnés parmi le groupe comprenant du PPh3, du P(o-tolyle)3, du P(2-furyle)3, P(OiPr)3, du CuI, du CuBr, de l'AsPh3 et de l'hydrure de di-i-butylaluminium (DIBAL), du 1,3-bis-diphénylphosphine-propane (DPPP) ou du 1,4-bis-diphénylphosphine-butane (DPPB).
- Procédé suivant l'une quelconque des revendications 1 à 3, dans lequel le catalyseur est généré in situ dans le récipient réactionnel dans lequel on réalise la réaction des composés de formule II et III.
- Procédé suivant l'une quelconque des revendications précédentes, dans lequel la réaction des composés de formule II et III et le transfert de métal du composé de formule (IV) sont réalisés en présence d'une forme de solvant qui est substantiellement non miscible à l'eau.
- Procédé suivant l'une quelconque des revendications précédentes, dans lequel la réaction des composés de formule II et III et le transfert de métal du composé de formule (IV) sont réalisés en présence d'un mélange de formes de solvants qui comprend une forme de solvant qui est substantiellement non miscible à l'eau et une forme de solvant sous forme d'un éther.
- Procédé suivant l'une quelconque des revendications précédentes, dans lequel le chlorure de zinc est utilisé comme agent de transfert de métal.
- Procédé suivant la revendication 8, dans lequel la réaction du composé de formule V avec du magnésium est réalisée en présence d'un solvant sous forme d'un éther.
- Procédé suivant la revendication 9, dans lequel au moins une partie du solvant éther présent pendant la réaction du composé de formule V avec du magnésium est conservée pendant la réaction du composé de formule IV avec l'agent de transfert de métal.
- Procédé suivant l'une quelconque des revendications 8 à 10, dans lequel les réactions des composés de formules IV et V et la génération in situ du catalyseur de palladium ou de nickel sont réalisées dans le même récipient réactionnel.
- Procédé suivant la revendication 11, dans lequel les réactions des composés de formules II, III, IV et V et la génération in situ du catalyseur de palladium ou de nickel sont réalisées dans le même récipient réactionnel.
- Procédé suivant l'une quelconque des revendications précédentes, comprenant l'étape ultérieure de déprotection du composé de formule I pour donner un composé de formule VI : ou un sel de celui-ci;
dans laquelle R1, R2, R3 et R4 sont chacun indépendamment un hydrogène, un alkyle en C1-C6, ou un perfluoroalkyle en C1-C6, R5 est un hydrogène ou R5 pris conjointement avec R3 forme une double liaison; m est 1, 2 ou 3; n est 0 ou 1, et p est 0, 1 ou 2. - Procédé suivant l'une quelconque des revendications précédentes, dans lequel m est 1, n est 0, p est 1, R1 et R2 sont chacun un méthyle et R3 et R4 sont chacun un hydrogène.
- Procédé suivant l'une quelconque des revendications précédentes, dans lequel X est un groupement alkyle en C1-C6 ou un groupement phényle ou benzyle, dans chaque cas facultativement substitué par un ou plusieurs substituants sélectionnés parmi des substituants alkyle en C1-C6, alcoxy en C1-C6, nitro, amino, (alkyl en C1-C6)amino, di(alkyl en C1-C6) amino, thio(alkyle en C1-C6) ou phényle.
- Procédé suivant la revendication 15, dans lequel X est un groupement alkyle en C1-C6 facultativement substitué par un ou plusieurs substituants sélectionnés parmi un alcoxy en C1-C6, un nitro, un amino, un (alkyl en C1-C6)amino, un di(alkyl en C1-C6)amino ou un thio(alkyle en C1-C6).
- Procédé suivant la revendication 16, dans lequel X est un t-butyle.
- Procédé suivant l'une quelconque des revendications précédentes, dans lequel R6 est un bromo.
- Procédé suivant l'une quelconque des revendications précédentes, dans lequel R8 est MgBr.
- Procédé suivant l'une quelconque des revendications précédentes, dans lequel R9 est un bromo.
- Procédé suivant la revendication 1, dans lequel le composé produit est la 8-[2'-(2(1)-t-butyl-2H-tétrazol-5-yl)biphényl-4-ylméthyl]-2,4-diméthyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (ou un composé de ce type dans lequel un groupement benzyle ou p-méthoxybenzyle est présent à la place du groupement t-butyle) ou un sel de celle-ci, ledit procédé étant caractérisé par(A) la réaction de 2-t-butyl-5-(2-bromo- ou iodophényl)-2H-tétrazole avec du magnésium pour donner le réactif de Grignard bromo- ou iodo[2-[2-(t-butyl)-2H-tétrazol-5-yl]phényl]magnésium,(B) le transfert de métal dudit réactif de Grignard avec du chlorure de zinc ou du bromure de zinc; et(C) la réaction du produit après transfert de métal avec de la 8-[(4-bromo- ou iodophényl)méthyl]]-5,8-dihydro-2,4-diméthylpyrido[2,3-d]pyrimidin-7(6H)-one en présence d'un catalyseur de palladium ou de nickel pour donner le produit;
- Procédé suivant la revendication 21, dans lequel le groupement t-butyle est utilisé.
- Procédé suivant la revendication 22, dans lequel le 2-t-butyl-5-(2-bromophényl)-2H-tétrazole est utilisé à l'étape A.
- Procédé suivant la revendication 21, dans lequel du chlorure de zinc est l'agent de transfert de métal à l'étape B.
- Procédé suivant la revendication 21, dans lequel on fait réagir de la 8-[(4-bromophényl)méthyl]-5,8-dihydro-2,4-diméthylpyrido[2,3-d]pyrimidin-7(6H)-one avec du chloro- ou bromo-[2-[2-(t-butyl)-2H-tétrazol-5-yl]phényl]zinc à l'étape C.
- Procédé suivant la revendication 21, dans lequel un catalyseur de palladium est utilisé à l'étape C.
- Procédé suivant la revendication 26, dans lequel le catalyseur de palladium est généré à partir de Pd(OAc)2 ou de PdCl2(PPh3)2 et d'un additif sélectionné parmi le groupe comprenant du PPh3, du P(o-tolyle)3, du P(2-furyle)3, P(OiPr)3, du CuI, du CuBr, de l'AsPh3 et du DIBAL.
- Procédé suivant la revendication 25, dans lequel un catalyseur de palladium phosphiné est généré dans le récipient réactionnel contenant le chloro- ou bromo-[2-[2-(t-butyl)-2H-tétrazol-5-yl]phényl]zinc.
- Procédé suivant la revendication 21, dans lequel la réaction des étapes B et C et la génération du catalyseur de palladium ou de nickel avec ou sans additif sont réalisées dans le même récipient réactionnel.
- Procédé suivant la revendication 1, dans lequel le composé produit est la 8-[2'-(2(1)-t-butyl-2H-tétrazol-5-yl)biphényl-4-ylméthyl]-2,4-diméthyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (ou un composé de ce type dans lequel un groupement benzyle ou p-méthoxybenzyle est présent à la place du groupement t-butyle) ou un sel de celle-ci, ledit procédé étant caractérisé par(B) le transfert de métal du réactif de Grignard bromo-[2-[2-(t-butyl)-2H-tétrazol-5-yl]phényl]magnésium avec du chlorure de zinc; et(C) la réaction du produit après transfert de métal avec de la 8-[(4-bromophényl)méthyl]]-5,8-dihydro-2,4-diméthylpyrido[2,3-d]pyrimidin-7(6H)-one en présence d'un catalyseur de palladium pour donner le produit;
- Procédé suivant l'une quelconque des revendications 21 à 30 comprenant l'étape suivante de déprotection du produit pour donner la 8-[2'-(1H-tétrazol-5-yl)biphényl-4-ylméthyl]-2,4-diméthyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one ou un sel de celle-ci.
- Composé suivant la revendication 32, dans lequel R10 est un t-butyle.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US47859295A | 1995-06-07 | 1995-06-07 | |
US478592 | 1995-06-07 | ||
US08/657,490 US5760220A (en) | 1995-06-07 | 1996-06-04 | Process for preparation of biphenyl derivatives |
US657490 | 1996-06-04 | ||
PCT/US1996/009117 WO1996040684A1 (fr) | 1995-06-07 | 1996-06-06 | Procede de preparation de derives de biphenyle |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0846117A1 EP0846117A1 (fr) | 1998-06-10 |
EP0846117B1 true EP0846117B1 (fr) | 2003-05-14 |
Family
ID=27045956
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP96918189A Expired - Lifetime EP0846117B1 (fr) | 1995-06-07 | 1996-06-06 | Procede de preparation de derives de biphenyle |
Country Status (15)
Country | Link |
---|---|
US (1) | US5977372A (fr) |
EP (1) | EP0846117B1 (fr) |
JP (1) | JPH11507625A (fr) |
CN (1) | CN1073110C (fr) |
AT (1) | ATE240325T1 (fr) |
AU (1) | AU718553B2 (fr) |
BR (1) | BR9609403A (fr) |
CA (1) | CA2223783A1 (fr) |
CZ (1) | CZ390097A3 (fr) |
DE (1) | DE69628175D1 (fr) |
EA (1) | EA000622B1 (fr) |
HU (1) | HUP9900871A3 (fr) |
IL (1) | IL122220A (fr) |
NZ (1) | NZ310164A (fr) |
WO (1) | WO1996040684A1 (fr) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1291356B1 (it) * | 1997-05-13 | 1999-01-07 | Zambon Spa | Processo per la rimozione di metalli pesanti |
IT1292437B1 (it) * | 1997-06-30 | 1999-02-08 | Zambon Spa | Processo di orto-metallazione utile per la sintesi di 1 - tetrazol- 5-il) benzeni 2-sostituiti |
NZ524806A (en) | 2000-10-23 | 2006-03-31 | Smithkline Beecham Corp | Tri-substituted 8H-pyrido[2,3-d]pyrimidin-7-one compounds |
GB0222056D0 (en) * | 2002-09-23 | 2002-10-30 | Novartis Ag | Process for the manufacture of organic compounds |
DE102004060699A1 (de) * | 2004-12-16 | 2006-06-22 | Ratiopharm Gmbh | Verfahren zur Herstellung von Candesartan |
UY29440A1 (es) | 2005-03-25 | 2006-10-02 | Glaxo Group Ltd | Nuevos compuestos |
EP2155759A4 (fr) * | 2007-05-07 | 2012-10-17 | Valorisation Rech Soc En Commandite | Méthodes de préparation de composés de diorganozinc |
US20220396576A1 (en) * | 2019-10-02 | 2022-12-15 | Blueprint Medicines Corporation | Process for preparing an activin receptor-like kinase inhibitor |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5039814A (en) * | 1990-05-02 | 1991-08-13 | Merck & Co., Inc. | Ortho-lithiation process for the synthesis of 2-substituted 1-(tetrazol-5-yl)benzenes |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5290780A (en) * | 1991-01-30 | 1994-03-01 | American Cyanamid Co. | Angiotensin II receptor blocking 2,3,6 substituted quinazolinones |
US5149699A (en) * | 1991-10-24 | 1992-09-22 | American Home Products Corporation | Substituted pyridopyrimidines useful as antgiotensin II antagonists |
EP0550313A1 (fr) * | 1991-12-30 | 1993-07-07 | Synthelabo | Nouveaux dérivés de 2-(tétrazol-5-yl)-(1,1'-biphényle), leur préparation et leur utilisation comme intermédiaires de synthèse |
US5466692A (en) * | 1993-03-24 | 1995-11-14 | American Home Products Corporation | Substituted pyridopyrimidines and antihypertensives |
-
1996
- 1996-06-06 JP JP9501516A patent/JPH11507625A/ja not_active Withdrawn
- 1996-06-06 CA CA002223783A patent/CA2223783A1/fr not_active Abandoned
- 1996-06-06 CZ CZ973900A patent/CZ390097A3/cs unknown
- 1996-06-06 WO PCT/US1996/009117 patent/WO1996040684A1/fr not_active Application Discontinuation
- 1996-06-06 DE DE69628175T patent/DE69628175D1/de not_active Expired - Lifetime
- 1996-06-06 AU AU60902/96A patent/AU718553B2/en not_active Ceased
- 1996-06-06 HU HU9900871A patent/HUP9900871A3/hu unknown
- 1996-06-06 EP EP96918189A patent/EP0846117B1/fr not_active Expired - Lifetime
- 1996-06-06 EA EA199800035A patent/EA000622B1/ru not_active IP Right Cessation
- 1996-06-06 CN CN96195896A patent/CN1073110C/zh not_active Expired - Fee Related
- 1996-06-06 IL IL12222096A patent/IL122220A/en not_active IP Right Cessation
- 1996-06-06 NZ NZ310164A patent/NZ310164A/xx unknown
- 1996-06-06 BR BR9609403A patent/BR9609403A/pt not_active Application Discontinuation
- 1996-06-06 AT AT96918189T patent/ATE240325T1/de not_active IP Right Cessation
-
1998
- 1998-02-27 US US09/032,129 patent/US5977372A/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5039814A (en) * | 1990-05-02 | 1991-08-13 | Merck & Co., Inc. | Ortho-lithiation process for the synthesis of 2-substituted 1-(tetrazol-5-yl)benzenes |
Also Published As
Publication number | Publication date |
---|---|
NZ310164A (en) | 2000-01-28 |
CA2223783A1 (fr) | 1996-12-19 |
HUP9900871A2 (hu) | 1999-07-28 |
DE69628175D1 (de) | 2003-06-18 |
EA199800035A1 (ru) | 1998-08-27 |
CZ390097A3 (cs) | 1998-06-17 |
HUP9900871A3 (en) | 2000-07-28 |
IL122220A0 (en) | 1996-06-06 |
AU718553B2 (en) | 2000-04-13 |
CN1073110C (zh) | 2001-10-17 |
BR9609403A (pt) | 1999-05-11 |
WO1996040684A1 (fr) | 1996-12-19 |
US5977372A (en) | 1999-11-02 |
JPH11507625A (ja) | 1999-07-06 |
EA000622B1 (ru) | 1999-12-29 |
ATE240325T1 (de) | 2003-05-15 |
AU6090296A (en) | 1996-12-30 |
CN1192214A (zh) | 1998-09-02 |
IL122220A (en) | 2001-08-08 |
EP0846117A1 (fr) | 1998-06-10 |
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